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  1. Article ; Online: Elucidating the Therapeutic Utility of Olaparib in Sulfatide-Induced Human Astrocyte Toxicity and Neuroinflammation.

    Mekhaeil, Marianna / Conroy, Melissa Jane / Dev, Kumlesh Kumar

    Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology

    2023  Volume 18, Issue 4, Page(s) 592–609

    Abstract: Metachromatic leukodystrophy (MLD) is a severe demyelinating, autosomal recessive genetic leukodystrophy, with no curative treatment. The disease is underpinned by mutations in the arylsulfatase A gene (ARSA), resulting in deficient activity of this ... ...

    Abstract Metachromatic leukodystrophy (MLD) is a severe demyelinating, autosomal recessive genetic leukodystrophy, with no curative treatment. The disease is underpinned by mutations in the arylsulfatase A gene (ARSA), resulting in deficient activity of this lysosomal enzyme, and consequential accumulation of galactosylceramide-3-O-sulfate (sulfatide) in the brain. Most of the effects in the brain have been attributed to the accumulation of sulfatides in oligodendrocytes and their cell damage. In contrast, less is known regarding sulfatide toxicity in astrocytes. Poly (ADP-ribose) polymerase (PARP) inhibitors are anti-cancer therapeutics that have proven efficacy in preclinical models of many neurodegenerative and inflammatory diseases, but have never been tested for MLD. Here, we examined the toxic effect of sulfatides on human astrocytes and restoration of this cell damage by the marketed PARP-1 inhibitor, Olaparib. Cultured human astrocytes were treated with increasing concentrations of sulfatides (5-100 μM) with or without Olaparib (100 nM). Cell viability assays were used to ascertain whether sulfatide-induced toxicity was rescued by Olaparib. Immunofluorescence, calcium (Ca
    MeSH term(s) Humans ; Sulfoglycosphingolipids ; Astrocytes ; Neuroinflammatory Diseases ; Poly(ADP-ribose) Polymerase Inhibitors/toxicity ; Reactive Oxygen Species ; Leukodystrophy, Metachromatic/genetics ; Leukodystrophy, Metachromatic/therapy
    Chemical Substances Sulfoglycosphingolipids ; olaparib (WOH1JD9AR8) ; Poly(ADP-ribose) Polymerase Inhibitors ; Reactive Oxygen Species
    Language English
    Publishing date 2023-11-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2227405-4
    ISSN 1557-1904 ; 1557-1890
    ISSN (online) 1557-1904
    ISSN 1557-1890
    DOI 10.1007/s11481-023-10092-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Olaparib Attenuates Demyelination and Neuroinflammation in an Organotypic Slice Culture Model of Metachromatic Leukodystrophy.

    Mekhaeil, Marianna / Conroy, Melissa Jane / Dev, Kumlesh Kumar

    Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics

    2023  Volume 20, Issue 5, Page(s) 1347–1368

    Abstract: Metachromatic leukodystrophy (MLD) is a severe demyelinating, autosomal recessive genetic leukodystrophy. The disease is underpinned by mutations in the arylsulfatase A gene (ARSA), resulting in deficient activity of the arylsulfatase A lysosomal enzyme ... ...

    Abstract Metachromatic leukodystrophy (MLD) is a severe demyelinating, autosomal recessive genetic leukodystrophy. The disease is underpinned by mutations in the arylsulfatase A gene (ARSA), resulting in deficient activity of the arylsulfatase A lysosomal enzyme and consequential accumulation of galactosylceramide-3-O-sulfate (sulfatide) in the brain. Using an ex vivo murine-derived organotypic cerebellar slice culture model, we demonstrate that sulfatide induces demyelination in a concentration-dependent manner. Interestingly, our novel data demonstrate that sulfatide-induced demyelination is underpinned by PARP-1 activation, oligodendrocyte loss, pro-inflammatory cytokine expression, astrogliosis, and microgliosis. Moreover, such sulfatide-induced effects can be attenuated by the treatment with the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Olaparib (IC50∼100 nM) suggesting that this small molecule may be neuroprotective and limit toxin-induced demyelination. Our data support the idea that sulfatide is a key driver of demyelination and neuroinflammation in MLD and suggest that PARP-1 inhibitors have therapeutic utility in the sphere of rare demyelinating disease.
    MeSH term(s) Animals ; Mice ; Leukodystrophy, Metachromatic/genetics ; Leukodystrophy, Metachromatic/metabolism ; Cerebroside-Sulfatase/genetics ; Cerebroside-Sulfatase/metabolism ; Sulfoglycosphingolipids/metabolism ; Neuroinflammatory Diseases ; Poly(ADP-ribose) Polymerase Inhibitors ; Demyelinating Diseases
    Chemical Substances Cerebroside-Sulfatase (EC 3.1.6.8) ; olaparib (WOH1JD9AR8) ; Sulfoglycosphingolipids ; Poly(ADP-ribose) Polymerase Inhibitors
    Language English
    Publishing date 2023-07-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2316693-9
    ISSN 1878-7479 ; 1933-7213
    ISSN (online) 1878-7479
    ISSN 1933-7213
    DOI 10.1007/s13311-023-01409-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6156: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  3. Article: Existing Evidence for the Repurposing of PARP-1 Inhibitors in Rare Demyelinating Diseases.

    Mekhaeil, Marianna / Dev, Kumlesh Kumar / Conroy, Melissa Jane

    Cancers

    2022  Volume 14, Issue 3

    Abstract: Over the past decade, Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have arisen as a novel and promising targeted therapy for breast cancer gene (BRCA)-mutated ovarian and breast cancer patients. Therapies targeting the enzyme, PARP-1, have since ... ...

    Abstract Over the past decade, Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have arisen as a novel and promising targeted therapy for breast cancer gene (BRCA)-mutated ovarian and breast cancer patients. Therapies targeting the enzyme, PARP-1, have since established their place as maintenance drugs for cancer. Here, we present existing evidence that implicates PARP-1 as a player in the development and progression of both malignancy and demyelinating disease. These findings, together with the proven clinical efficacy and marketed success of PARP-1 inhibitors in cancer, present the repurposing of these drugs for demyelinating diseases as a desirable therapeutic concept. Indeed, PARP-1 inhibitors are noted to demonstrate neuroprotective effects in demyelinating disorders such as multiple sclerosis and Parkinson's disease, further supporting the use of these drugs in demyelinating, neuroinflammatory, and neurodegenerative diseases. In this review, we discuss the potential for repurposing PARP-1 inhibitors, with a focus on rare demyelinating diseases. In particular, we address the possible use of PARP-1 inhibitors in examples of rare leukodystrophies, for which there are a paucity of treatment options and an urgent need for novel therapeutic approaches.
    Language English
    Publishing date 2022-01-29
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers14030687
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Investigating the Effects of Olaparib on the Susceptibility of Glioblastoma Multiforme Tumour Cells to Natural Killer Cell-Mediated Responses.

    Moran, Jennifer / Mylod, Eimear / Kane, Laura E / Marion, Caroline / Keenan, Emily / Mekhaeil, Marianna / Lysaght, Joanne / Dev, Kumlesh K / O'Sullivan, Jacintha / Conroy, Melissa J

    Pharmaceutics

    2023  Volume 15, Issue 2

    Abstract: Glioblastoma multiforme (GBM) is the most common adult primary brain malignancy, with dismal survival rates of ~14.6 months. The current standard-of-care consists of surgical resection and chemoradiotherapy, however the treatment response is limited by ... ...

    Abstract Glioblastoma multiforme (GBM) is the most common adult primary brain malignancy, with dismal survival rates of ~14.6 months. The current standard-of-care consists of surgical resection and chemoradiotherapy, however the treatment response is limited by factors such as tumour heterogeneity, treatment resistance, the blood-brain barrier, and immunosuppression. Several immunotherapies have undergone clinical development for GBM but demonstrated inadequate efficacy, yet future combinatorial approaches are likely to hold more promise. Olaparib is FDA-approved for BRCA-mutated advanced ovarian and breast cancer, and clinical studies have revealed its utility as a safe and efficacious radio- and chemo-sensitiser in GBM. The ability of Olaparib to enhance natural killer (NK) cell-mediated responses has been reported in prostate, breast, and lung cancer. This study examined its potential combination with NK cell therapies in GBM by firstly investigating the susceptibility of the GBM cell line T98G to NK cells and, secondly, examining whether Olaparib can sensitise T98G cells to NK cell-mediated responses. Here, we characterise the NK receptor ligand profile of T98G cells and demonstrate that Olaparib does not dampen T98G susceptibility to NK cells or elicit immunomodulatory effects on the function of NK cells. This study provides novel insights into the potential combination of Olaparib with NK cell therapies for GBM.
    Language English
    Publishing date 2023-01-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527217-2
    ISSN 1999-4923
    ISSN 1999-4923
    DOI 10.3390/pharmaceutics15020360
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons.

    Brunialti, Electra / Villa, Alessandro / Mekhaeil, Marianna / Mornata, Federica / Vegeto, Elisabetta / Maggi, Adriana / Di Monte, Donato A / Ciana, Paolo

    Journal of neuroinflammation

    2021  Volume 18, Issue 1, Page(s) 220

    Abstract: Background: Homozygotic mutations in the GBA gene cause Gaucher's disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson's disease. In homozygosis, these mutations ... ...

    Abstract Background: Homozygotic mutations in the GBA gene cause Gaucher's disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson's disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher's disease. Notwithstanding the key role of macrophages in this disease, most of the effects in the brain have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported.
    Methods: We applied the bioluminescence imaging technology, immunohistochemistry and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia cocultures and in cell lines. The use of primary cells from reporter mice allowed for the first time, to discriminate in cocultures neuronal from microglial responses consequent to the β-glucocerebrosidase inhibition; results were finally confirmed by pharmacological depletion of microglia from the brain of mice.
    Results: Our data demonstrate the existence of a novel neuroprotective mechanism mediated by a direct microglia-to-neuron contact supported by functional actin structures. This cellular contact stimulates the nuclear factor erythroid 2-related factor 2 activity in neurons, a key signal involved in drug detoxification, redox balance, metabolism, autophagy, lysosomal biogenesis, mitochondrial dysfunctions, and neuroinflammation. The central role played by microglia in this neuronal response in vivo was proven by depletion of the lineage in the brain of reporter mice. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, to turn on an anti-inflammatory/repairing pathway, and to hinder the microglia ability to activate the nuclear factor erythroid 2-related factor 2 response, thus increasing the neuronal susceptibility to neurotoxins.
    Conclusion: This mechanism provides a possible explanation for the increased risk of neurodegeneration observed in carriers of GBA mutations and suggest novel therapeutic strategies designed to revert the microglial phenotype associated with β-glucocerebrosidase inhibition, aimed at resetting the protective microglia-to-neuron communication.
    MeSH term(s) Animals ; Brain/enzymology ; Brain/pathology ; Cell Communication/physiology ; Glucosylceramidase/antagonists & inhibitors ; Mice ; Microglia/enzymology ; Microglia/pathology ; Neurons/metabolism ; Neurons/pathology ; Neuroprotection/physiology
    Chemical Substances Glucosylceramidase (EC 3.2.1.45)
    Language English
    Publishing date 2021-09-22
    Publishing country England
    Document type Journal Article
    ZDB-ID 2156455-3
    ISSN 1742-2094 ; 1742-2094
    ISSN (online) 1742-2094
    ISSN 1742-2094
    DOI 10.1186/s12974-021-02272-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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